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Reporting of cross-over clinical trials of analgesic treatments for chronic pain: Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks systematic review and recommendations

Gewandter, Jennifer S.; McDermott, Michael P.; McKeown, Andrew; Hoang, Kim; Iwan, Katarzyna; Kralovic, Sarah; Rothstein, Daniel; Gilron, Ian; Katz, Nathaniel P.; Raja, Srinivasa N.; Senn, Stephen; Smith, Shannon M.; Turk, Dennis C.; Dworkin, Robert H.

doi: 10.1097/j.pain.0000000000000673
Research Paper

Cross-over trials are typically more efficient than parallel group trials in that the sample size required to yield a desired power is substantially smaller. It is important, however, to consider some issues specific to cross-over trials when designing and reporting them, and when evaluating the published results of such trials. This systematic review evaluated the quality of reporting and its evolution over time in articles of cross-over clinical trials of pharmacologic treatments for chronic pain published between 1993 and 2013. Seventy-six (61%) articles reported a within-subject primary analysis, or if no primary analysis was identified, reported at least 1 within-subject analysis, which is required to achieve the gain in power associated with the cross-over design. For 39 (31%) articles, it was unclear whether analyses conducted were within-subject or between-group. Only 36 (29%) articles reported a method to accommodate missing data (eg, last observation carried forward, n = 29), and of those, just 14 included subjects in the analysis who provided data from only 1 period. Of the articles that identified a within-subject primary analysis, 21 (51%) provided sufficient information for the results to be included in a meta-analysis (ie, estimates of the within-subject treatment effect and variability). These results and others presented in this article demonstrate deficiencies in reporting of cross-over trials for analgesic treatments. Clearer reporting in future trials could improve readers' ability to critically evaluate the results, use these data in meta-analyses, and plan future trials. Recommendations for proper reporting of cross-over trials that apply to any condition are provided.

Supplemental Digital Content is Available in the Text.Although improvements have occurred, deficiencies in reporting of analgesic cross-over trials are still prevalent. Reporting recommendations are provided to promote clearer reporting in future trials.

aDepartment of Anesthesiology University of Rochester, Rochester, NY, USA

bDepartment of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, USA

cCity University of New York-Hunter College, New York City, NY, USA

dDepartment of Pain Medicine, MD Anderson Cancer Center, Houston, TX, USA

eDepartment of Anesthesiology, Queen's University, Kingston, ON, Canada

fAnalgesic Solutions, Natick, MA, USA

gTufts University, Boston, MA, USA

hDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA

iLuxembourg Institute of Health, Strassen, Luxembourg

jDepartment of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA

Corresponding author. Address: University of Rochester, 601 Elmwood Ave., Box 604 Rochester, NY 14642, USA. Tel.: +1 585 276 5661; fax: +1 585 244 7271. E-mail address: (J. S. Gewandter).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received February 25, 2016

Received in revised form June 06, 2016

Accepted July 13, 2016

© 2016 International Association for the Study of Pain
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